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New drug stirs scientists' hopes of halting AIDS Thu, 01 Mar 2007 01:01:00 EST An experimental AIDS drug, years in the making by scientists from Johnson & Johnson and Rutgers University, is part of an assortment of startlingly effective new treatments shown to zap resistant strains of HIV. Scientists from J&J's Tibot... - NJ: Star-Ledger (Article) : Read More

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New drug stirs scientists' hopes of halting AIDSThursday, March 01, 2007 BY KITTA MacPHERSONStar-Ledger Staff An experimental AIDS drug, years in the making by scientists from Johnson & Johnson and Rutgers University, is part of an assortment of startlingly effective new treatments shown to zap resistant strains of HIV.

Scientists from J&J's Tibotec division reported the results yesterday at the end of a major AIDS conference in Los Angeles. The drug, TMC-278, has long been viewed as the most promising of a family of revolutionary AIDS compounds called "DAPY" (rhymes with "happy') being developed by the New Brunswick drug giant.

"Right now, it looks as if this could be a home run for patients," said Roger Pomerantz, president of J&J's Tibotec Pharma Ltd. in Yardley, Pa., minutes after a presentation before a standing-room-only crowd of 4,000. "I am very jazzed about this. It's going to have a huge impact."

The J&J AIDS presentation followed a equally riveting talk by scientists from Gilead Sciences Inc. in California on their treatment advances, as well as announcements on Tuesday by Merck & Co. of Whitehouse and Pfizer of New York of major strides in AIDS treatment. All of the new drugs attack difficult-to-treat "resistant" strains of the virus and that news has energized the AIDS community.

"It's a brand-new day," said Stephen Smith, a physician-scientist who directs the department of infectious disease at Saint Michael's Medical Center in Newark. "This means that no one in the developed world should be walking around anymore with any detectable levels of virus in their blood. These drugs are just blowing me away."

The announcements made at the 14th annual Conference on Retroviruses and Opportunistic Infections, according to Smith and other experts, are as revolutionary as the breakthroughs of the mid-1990s when scientists developed drug cocktails to stop AIDS.

Merck's drug, MK-0518, blocks an enzyme called integrase that helps the virus replicate. The company plans to seek federal approval before July 1 to use the drug against resistant HIV, the deadly virus that causes AIDS. Gilead also presented promising results from tests on its integrase inhibitor, GS-9137, which is in second-stage testing.

Pfizer's HIV pill, named maraviroc, is the first of a new class of medicines called CCR5 inhibitors that block a chemical doorway used by the virus to infect cells. A chemical cocktail that included maraviroc suppressed the drug in patients who do not respond to older treatments, scientists reported.

Resistant strains, caused when the quick-change artist that is HIV morphs its shape and structure to survive lethal drug attacks, is a huge and growing medical problem. About 10 percent of new HIV patients are infected with a virus resistant to at least one type of AIDS drug, according to a study released earlier this week by the federal Centers for Disease Control and Prevention in Atlanta. And five people in 1,000, according to the study, suffer from a form that evades all three major AIDS therapies currently available.

TMC-278 ("Tibotec medical compound") is a non-nucleoside reverse transcriptase inhibitor. Like other drugs in this category, it jams the machinery of reverse transcriptase, one of the prime proteins responsible for the reproduction of HIV.

That dream and Arnold's team ultimately produced R278474 or ripilvirine, Janssen's favorite anti- AIDS compound and the newest DAPY. The compounds are so named because they have diarylpyrimidine at their core. The other two compounds -- dapivirine or TMC-120, and etravirine or TMC- 125 -- have gone through early phases of clinical trials. Making it through those experiments, something most drugs don't accomplish, shows the compounds hold great promise to win federal approval.

Details of R278474 will be published early next year in an issue of the Journal of Medicinal Chemistry to be dedicated to "Dr. Paul," as the Belgian physician-scientist was known to colleagues. (On Nov. 11, Arnold's team pre-published details in the electronic edition of the Journal of Medicinal Chemistry. The article represents the pinnacle of their work.)

R278474 never would have existed without Janssen's work 14 years earlier.

In 1990, he published a paper in the science journal Nature describing a new drug that blocked HIV's key protein, reverse transcriptase. Problem was, the compounds caused resistant strains to pop up too quickly, infecting cells with offspring that had tiny mistakes in their genetic code. That meant drugs designed to target a specifically formed virus could fail to recognize and treat mutant strains.

Unable to see this relationship between the drug and the killer virus under a microscope, Janssen needed a scientist to make a crystal that would combine reverse transcriptase with his experimental compound. He was told there were only three people who could do it.

Arnold was one of them.

Together -- along with Hughes and other determined colleagues -- they embarked on a journey under the banner of modern molecular biology, a discipline defined by DNA co-discoverer Francis Crick as "the attempt to understand any biological problem at the level of atoms and molecules."

For the next decade, they talked weekly, sometimes daily. First, they would need to understand RT. Then, they could start working on the mysteries of RT inhibitors. Hughes provided RT; Janssen, the inhibitors, and Arnold eventually brought it all together with his crystals.

CRYSTAL GAZINGCrystallography, which involves rendering materials into well-ordered crystals and then fathoming their atomic structures, may be as much art as science.

The Picasso that Arnold's lab was chasing was the crystal structure of reverse transcriptase.

"It took us from 1987 until mid- 1991 to get RT crystals that were useful for getting a detailed structure," Arnold said. "But it took until mid- to late 1992 to solve the detailed structure from these crystals. It was very technically challenging."

Even if a molecule is too tiny to see with a microscope, a crystallographer can figure out its shape and composition -- what scientists call its structure.

About 2 a.m. one spring night in 2000, Rutgers University physicist- turned-crystallographer Kalyan Das was sitting before a computer monitor in the basement of his Edison townhouse.

He stared at an image of a DAPY drug -- TMC-120 -- that had been shown in lab studies by scientists at Tibotec Virco. There was a hitch, though: The people who made the compound did not yet understand exactly how it worked.

How is it, Das wondered, that the compound could fit so neatly into the cleft of so many versions of the viral protein, effectively blocking its copying action? To do this, the molecule he was viewing had to wiggle.

Just then, he thought back to his childhood, to the winding caves near a Hindu temple his family attended in India. He remembered how he had to twist and turn to make it back toward the light.

Das then reasoned that the atoms at the extreme end of the compound exhibited "torsional flexibility," like the movement of a gate swinging on hinges attached to a post. The molecule, he ventured, also had to jiggle, or rock lightly. In short, the compound seemed to be flexible.

Das was excited.

A drug that could wiggle and jiggle -- acting like a master key -- would be groundbreaking.

The Rutgers group had kicked around the idea of molecular nimbleness for a couple of years and several earlier compounds had shown some degree of bending. But nothing had acted like this. Now it would be the team's job to use crystallography to figure out exactly how the DAPYs worked.

The light is a million times brighter than sunlight and a billion times greater than the radiation from a typical lab X-ray.

The emerging beams are just a few thousandths of a millimeter across and are emitted in extremely short pulses, typically 10 to 100 picoseconds (trillionths of a second) in length. The beams barely scrape the precious crystals.

Colleagues often told Das he had a velvet touch with the synchrotron. When others brought dozens of crystals and left without relevant data, Das brought one or two and always got results. That is, until he ran into DAPY.

For more than a year, Das blasted through hundreds of crystals at CHESS and other synchrotrons. Still, he could not obtain useful data.

In the fall of 2003, after a year of fine-tuning, testing and writing, editors at both Science and Nature rejected Das' paper on the work, saying it was focused on drug development and not of sufficient general interest. The team took it hard, especially since, as Arnold put it, the work may be "the best thing we've ever done."

With nearly two decades invested, they had little choice but to forge ahead and run experiments to understand what made the DAPY drugs work so well. They also studied the mechanism of resistance in RT -- how it occurs, step by step, on a molecular level.

Finally, Das published the results of the team's work on the DAPY crystal in May 2004 in the Journal of Medicinal Chemistry. By summer, molecular flexibility was the talk of a meeting at the National Institutes of Health. It remains a popular theme among researchers. "We may eventually win the war against HIV/AIDS. That would be an extremely rewarding and satisfying outcome," he said. "But even to have contributed to helping the health and well-being of the many people infected by HIV will be very satisfying if that were to happen."

Until then, the clock continues ticking as Arnold and his team work on their latest project, an AIDS vaccine -- one of the most difficult-to-achieve scientific goals in history.

"Only the impossible is worth doing," Arnold said. To change the world, Eddy Arnold has always tried to think small.

For nearly 20 years, the Rutgers University chemist has obsessively dismantled the AIDS virus to untangle its deadly submicroscopic machinery.

And it is there, in the complex world of the minuscule, he believes he finally has found a magic bullet that stops AIDS in its tracks.GRAPHICS

• How HIV works/Resistance and DAPY compounds (PDF)

• X-ray crystallography(PDF)

Arnold and his coterie of researchers have developed what they regard as three revolutionary AIDS drugs, each part of a family they call DAPY (which rhymes with happy).

The drugs, they believe, can destroy HIV, the deadly virus that causes AIDS.

To do this, the drugs do as HIV does when it devours immune systems: They change shape. Put another way, DAPYs are a master key that can fit any strand of the virus, regardless of how it tries to disguise itself.

As Arnold says: "We're onto something very, very special."

Understanding and controlling this flexibility in a treatment is crucial because HIV's biggest challenge to science and medicine has been its ability to consistently mutate, outrunning any drug or vaccine custom-designed to quash it. And unlike other treatments that focus on blocking HIV from entering healthy cells or from containing contaminated ones, DAPYs literally douse a lit firecracker by interfering with any of the 20,000 steps HIV takes to copy itself at warp speed.

At the core of this discovery is reverse transcriptase -- the villain in this story and a submicroscopic protein not normally found in healthy human cells. The team believes RT is the ideal protein to disable because it offers so many opportunities to be blocked.

The most promising of the three DAPY drugs in the family is a new supercompound known as R278474.

Because DAPYs can be delivered in just one pill instead of the present drug cocktail taken by millions of AIDS patients, Arnold and others believe, they are another step toward the goal of creating a cheaper, more effective way to stay ahead of the epidemic.

So far, tests conducted internally at New Brunswick-based Johnson & Johnson indicate the drug is a snap to synthesize, is easily absorbed with minimal side effects and shows promise as a once- daily, low-dose oral treatment.

For researchers on the front line, R278474 and its cousins may be that magic bullet.

"This could be it," said Stephen Smith, a physician/scientist who directs the department of infectious disease at St. Michael's Medical Center in Newark. "We're all looking for the next class of drugs."

Smith manages dozens of clinical trials testing AIDS treatments and said the idea underlying the new RT inhibitors makes sense.

I have to ask. If the DAPY compound is so flexible and able to modify it's shape to "Jam" HIV, then why are we on HAART with this new compound? I mean, why are we on multiple drugs? Wouldn't this mean that "resistance is futile?"

If the DAPY Compound can "wiggle" and handle all strains, then doesn't this open the door to mono therapy? And from what I understand, this new TMC-278 competes with Sustiva but minus the mind games. Is this the end to resistance?